Anthrax has re-emerged as a serious bioterrorist threat. Inhalational anthrax is usually fatal if not identified early enough for antibiotics to be of use. The lethality is primarily due to the effects of the toxins.
Anthrax toxin, which consists of three polypeptides protective antigen (PA or PAw, 83 kDa), lethal factor (LF, 90 kDa) and edema factor (EF, 89 kDa), is a major virulence factor of Bacillus anthracia. The LF and EF components are enzymes that are carried into the cell by PA. The combination of PA and LF forms lethal toxin. Anthrax toxin enters cells via a receptor-mediated endocytosis. PA binds to the receptor and is processed (PA, 63 kDa), which forms a heptameric ring that delivers the EF or LF to the cytosol. The path leading from PA binding to cells via TEM-8 or CMG2, furin processing, heptamer formation, LF or EF binding to heptamer, or the translocation of EF/LF to the cytosol provides multiple sites for molecular intervention.
Mouse monoclonal antibodies neutralize anthrax toxin in vivo in rat (Little et al., 1990 Infect Immun 58:1606-1613). Rabbit anti-PA given 24 hours post-infection protects 90% of the infected guinea pigs (Kobiler et al. 2002 Infect Immun 70:544-550). Domain 4 of PA contains the dominant protective epitopes of PA (Flick-Smith et al. 2002 Infect Immun 70:1653-1656). Protection against anthrax toxin by anti-PA monoclonal antibodies correlates strongly with affinity (Maynard et al. 2002 Nat Biotechnol 20:597-601).